Historical Review and Recent Advances
in Neonatal and Perinatal Medicine

Edited by George F. Smith, MD and Dharmapuri Vidyasagar, MD
Published by Mead Johnson Nutritional Division, 1980
Not Copyrighted By Publisher

Chapter 11

Birth Asphyxia

Phillip J. Goldstein, M. D.

The examination of birth asphyxia from a historical perspective
presents several intriguing problems. First, of course, there is no
satisfactory definition. Clinicians, biochemists and pathologists all
seem to use the phrase, but a universal definition is lacking. Dr.
Eastman of Hopkins called asphyxia "an infelicity of etymology" since
the Greek derivation of asphyxia meant "without pulse." A second
problem seems to be that, within each specialty studying asphyxia,
once a definition is established, the exceptions are enormous. For
instance, to the pathologist, a defined "asphyxic" lesion may occur
without any clinical or biochemical history of asphyxia. The term
asphyxia when defined in physiology textbooks includes hypoxia plus
hypercarbia. Alternatively, biochemical evidence of asphyxia is
present in tremendous numbers of children who, in fact, are
clinically completely normal.

A recent pair of published papers from the University of
Pittsburgh describe the effects of neonatal asphyxia on children. The
investigators demonstrated the relationship between prematurity and
asphyxia, and showed the positive relationship between survival and
gestational age.[1] They reconfirmed the finding
that the incidence and severity of birth asphyxia complications were
not related to gestational age. This information was not especially
new. What is intriguing about these papers, however, is the criterion
used for diagnosis of asphyxia. In an age where technological advance
is a daily occurrence, and where intricate cellular physiology is
being studied in detail, these investigators used as their sole
criterion for the diagnosis of asphyxia, "infants who required more
than one minute of positive pressure ventilation before sustained
respiration occurred." The specific etiology leading to the absence
of voluntary respiratory effort is not mentioned, nor is any
reference made to blood biochemistry!

Research literature in birth asphyxia and its sequelae abounds
with the names of truly superb investigators. The predominant goal of
their research, however, has been the elucidation of mechanisms both
macroscopic and cellular. Although this research is voluminous, the
total impact on direct care, diagnostically and therapeutically, is
very limited with respect to human application.

Lastly, it is also fair to state that perspective improves over
time. It is, therefore, my intention to explore the past with greater
abandon than the present. The acuity of one's perception is commonly
befuddled concerning recent events. Bias and personal value systems
can dim any of our judgments, a phenomenon obvious in the history of
the retrolental fibroplasia (RLF) epidemic as described by William
Silverman.[2] Such bias is also very apparent in
the refusal of physicians to accept the physician vector concept of
the transmission of streptococci on puerperal fever in the mid
1800's.[3]

Dr. William Little presented his paper defining a causal
relationship between abnormal parturition and central nervous system
damage in 1861. Dr. Little cautioned that the difference between
apoplexy, asthenia and asphyxia was unknown but that in asphyxia,
circulatory failure was clearly a factor and an important cause of
the central nervous system (CNS) clinical pathology .4 In
fact, his talk to the Obstetric Society of London was the culmination
of a long series of studies published, in part, in Lancet
beginning several years earlier. He mentioned other authors who
characterized and commented on the immediate neonatal period but then
he stated "they seem quite unaware; that abnormal parturition besides
ending in death or recovery, not infrequently has another termination
. . . in other diseases."

The expressions in vogue to describe birth asphyxia in Little's
time included "asphyxia neonatorum" and "suspended animation," a
descriptive term not terribly different from the 1980 Pittsburgh
author's! He compared the appearance of these newborn children
suffering from asphyxia to adult drowning victims. He certainly
visited the autopsy area frequently to correlate the clinical
findings and he traced the pathology of such infants who die to brain
stem lesions. By contrast, a famous American physician is quoted in
Dr. Little's article. J. Marion Sims, the founder of the Women's
Hospital of the state of New York, the first American institution
devoted to gynecologic diseases, attached "no importance to either
tedious labour or to asphyxia at birth."

A survey of Little's 47 cases reveals a melange of pathology but
is illustrative of his times. Children in those days were born,
swaddled, and prayed for. Days could pass without their giving
evidence of much life. In fact, during the spirited discussion which
followed Little's paper, the intellectual giant, Samuel Johnson, who
had "nervous disorders," was described as being "dead at birth." The
Society members who heard Dr. Little were clearly enthusiastic about
his thesis and the article ends by noting that Richard III was a
premature breech which might have accounted for some of his well
known physical and behavioral deficiencies.

Little's thesis included an allusion to the difference between
asphyxia pallida and asphyxia livida with the former
the much more ominous event. Most interesting from the historical
perspective is his observation that "it is obvious that the great
majority of apparently stillborn infants whose lives are saved by the
attendant accoucheur recover unharmed from that condition." Dr.
Little, being a courtly speaker and author, excused the physicians
who practiced midwifery from antedating his observations. He bemoaned
the fact that a proper lying-in hospital was needed, and felt that
his observations would be extended and supported by such a facility.
Dr. Little was eminently qualified to discuss the advantage of
specialized medical facilities. He founded the Royal Orthopedic
Hospital. He also, it must be stated, was familiar with the politics
and strife of administration. In a long and obviously aggravating
series of articles, starting in 1851, in Lancet, he engaged in
a public confrontation with one of the board members of the charity
which solicited the original money for the Orthopedic Hospital. The
board member opponent was claiming primacy as the founder and wanted
recognition of the fact. The board member stated that he had proof,
since his portrait was the first one hung in the board room. Needless
to say, Little prevailed.

In reviewing the history of birth asphyxia, one name in perinatal
medicine which should be central is that of N. J. Eastman. Eastman's
contributions to birth asphyxia are of inestimable value. Dr.
Eastman's work began in the early 1930's and was based on sound
physiologic principles derived from the great physiologists who were
working in the area of respiration at that time. Dr. Eastman defined
asphyxia as "an inability of the child to breathe and apnea
associated with oxygen deficiency during labor." It was this very
issue, the initiation of respiration at birth, that stimulated Dr.
Eastman's original contributions. Dr. Eastman was vitally interested
in the concept of whether hypercarbia or hypoxia was responsible for
the initiation of respiration.[5] He was aware of
the work of Barcroft and others in England, including Hugget's work
with goats. He felt that only by understanding the normal initiation
of human respiration and the biochemistry involved at the time of
initiation of respiration, could we know the abnormalities associated
with abnormal respiration, i.e. asphyxia. His studies proceeded in a
series of five articles published between 1931 and 1936. He first
studied the oxygen concentration and oxygen delivery of maternal and
fetal blood through the umbilical vein and the return of blood to the
mother via the umbilical artery, in 16 patients. The details involved
in collecting the blood, and the mechanisms, are remarkable. He
guessed, as a result of his experiments, that there was likely
intrauterine cyanosis (!) but that the minimal oxygen unloading was
sufficient for a dormant, thermostable organism.

His next paper used these 16 patient models as controls for the
identification of deviations from normal. He measured lactate in cord
blood of 24 patients, 7 of whom had birth asphyxia.' Three of these
infants died and he reported that at autopsy they had no evidence of
trauma or hemorrhage. He showed the maternal-fetal lactate
relationships and indicated that this was likely a measure of mild
oxygen deficiency. He stated that the absence of hyperlactatemia
demonstrated fetal oxygen adequacy. He quoted a paper by Heinbicken,
a German investigator, who in 1929 demonstrated that cellular acidic
products generated from anoxemia could cause cellular damage! The
summary of these two inquiries and their clinical application is
encompassed by Eastman's third paper on the
subject.[7] He quoted the Kane and Kreiselman
study of 1930 showing increased carbon dioxide in the blood of
asphyxiated adult patients. Dr. Eastman then measured the carbon
dioxide and pH in normal and abnormal fetal and maternal blood.
Lastly, he demonstrated that neonatal acidosis accompanies asphyxia.

Schmidt in 1928 had published a theory of "reversal" of which
Eastman knew.[8] Schmidt stated that after
prolonged oxygen deprivation and acidemia including hypercarbia,
cerebral cells, including the respiratory center, no longer could
utilize oxygen and, rather than stimulating increased respiratory
activity, respiratory depression ensued. Mathison in 1910 had
demonstrated the effect of asphyxia on reducing cardiac output. Dr.
Eastman postulated from this pathophysiologic observation that the
well known ominous process of asphyxia pallida equalled circulatory
failure.[9] Eastman then concluded that high
carbon dioxide or low oxygen were not the primary initiators of
respiration. He also made very clear that the goals for resuscitation
are evident! He wrote, "There seems to be only one urgent indication
in the treatment of asphyxia neonatorum, and that is to introduce
oxygen into the circulating blood o£ the infant." He continued
"that the usual forms of stimulation (including slapping, bathing and
carbon dioxide inhalation) produce depression . . . and may
even result in irreparable damage to the brain cells."

A subsequent paper apparently was the first to identify the human
alterations of fetal hemoglobin on oxygen affinity as compared to the
adult hemoglobin and its oxygen affinity.[10]

Dr. Eastman's investigations then led him into an inquiry into the
role of anesthesia in neonatal depression and production of
asphyxia.[9] In the 1930's, there was considerable
suspicion which indicated that part of the narcosis associated with
the administration of anesthetic agents was the hypoxia associated
with their use, and that the hypoxia was as responsible for the
central nervous system depression as was the agent itself. Dr.
Eastman proceeded to look at the oxygen concentrations in both
mothers and babies and came to the conclusion that under most
circumstances depression seen following anesthesia in the neonate is,
in fact, not related to oxygen deficiency but is related to the drug
used. He urged caution, however, and agreed that the inappropriate
concentrations o£ drugs resulted in apnea due to asphyxia, not
apnea due to anesthesia. It was this distinction that was probably
the first great scientific differentiation made in modern day
perinatal medicine concerning respiratory neonatal
depression.[10,11,12]

No review of birth asphyxia can ignore the Apgar score. Dr. Apgar,
in her original paper published in 1953, was obviously disturbed by
the lack of specificity in resuscitation.[13]She
decried the lack of systematic evaluation of newborns which limited
the evaluation of resuscitation methodology. She chose her criteria
in part to obviate the need for intervention during the resuscitation
efforts and felt that her criteria could be delineated without
compromising care. She then correlated her score with a variety of
birthing variables including perinatal mortality and type of
anesthesia, and showed the inverse relationship of the score to the
need for active resuscitative needs. She clearly did not intend to
have her score used to do more than focus attention on the baby and
its immediate needs, as well as to objectify and systematize the
process for observer communications.

Dr. Apgar's work was extended by several of her associates,
notably Dr. L. S. James. James and his coworkers converted the
pathophysiology of the Apgar criteria into human acid-base
biochemical correlates.[14] On this latter
subject, Dr. James and his group performed a notable service. Since
one of the weaknesses of historical observation in asphyxia is the
lack of coordination among clinical, biochemical and pathological
phenomena, this less dramatic work is of critical importance.

It is difficult to ignore the relationship of lower animal
research to human pathology. Most of the great bench researchers in
the area of birth asphyxia applied qualifiers to their research and
cautioned against over-interpretation. Dr. Louis Gluck, in prefacing
his superb symposium on intrauterine asphyxia, alluded to the problem
with reference to the heart rate quantification controversy of the
early 1960's. "Bench laboratory" researchers had trouble confirming
Dr. Edward Hon's work in humans. Gluck wrote, "This was the classic
example of a faulty basic premise carried out to an untenable
conclusion. "[16]

Although many investigators have contributed to the mystery of
mechanisms in asphyxia, Dr. William Windle deserves special
mention.[15] Primarily because of his methodology
and his gradual decision to use the subhuman primate as a model, much
of the pathophysiology of the sequelae of asphyxia is clearer. Dr.
Windle has published two excellent summaries of his research as well
as dozens of papers.[16,17] He also was
responsible for developing an extraordinary multidisciplinary effort
in Puerto Rico, in conjunction with Pierce Bailey. The intense
environment, coupled with the concentration of several fine minds,
was phenomenal not only in terms of content but in range of
exploration. During its 15 year history, the lab was visited by many
of the most productive fetal physiologists in the world and served as
a training area in both perinatal and neonatal care for many young
investigators. Dr. Ron Meyers eventually followed Windle and became
the primary investigator in the Puerto Rico project from 1964-1970
when the lab closed. His work is most notable because it reflects the
summation of the most important correlates between clinical state,
biochemical measures and pathological findings. Dr. Meyers described
the cycle of hypoxia leading to lactate dependent cellular damage
which is likely causal in brain damage. As the cells swell with
secondary loss of membrane transfer integrity, ischemia occurs,
further decreasing oxygen delivery. Since, simultaneously,
cardiac muscle is being affected, resulting in reduced cardiac
output, further hypoperfusion occurs.[18]
(Remember that such cardiac data predicting reduced cardiac output
first appeared around 1910!) It seemsfair to say that these
laboratory findings built upon empiric human data such as that of
Little, careful clinical observation as exemplified by Eastman, and
systemization as developed by Apgar, resulted in altered approaches
to both resuscitation and prevention.

It is from a more current historical perspective that Dr. Edward
Hon is mentioned.[19] Dr.
Hammacher[21] and Dr.
Calderyo-Barcia[20] also deserve historical
consideration relative to diagnosis of intrapartum distress. Since
the goal of observed pathophysiology should be prevention, based on
the understanding of the involved mechanisms, the work of theseinvestigators must be considered central. Unfortunately many
exaggerated claims for the value of fetal monitoring using
inappropriate or absent controls have been made. The magnificent
obstetrical inconoclast, Dr. Robert Goodlin, in his remarkable
article on fetal monitoring quotes Shakespeare: "All that glitters is
not gold," with reference to fetal monitoring.[22]
His cynicism is justifiable in that many confounding variables, such
as marked improvement in neonatal care and increased risk assessment,
became operative essentially simultaneously with the development of
continuous fetal monitoring. But omit the argument whether the exact
information derived distinguishes "benign" from "malignant" patterns,
the absence of patterns is clearly reassuring and a valid indicator
of fetal well being. Alternatively, abnormal heart rate is very
positively correlated with both poor outcome and fetal acidemia. The
current problem, from a historical perspective, then becomes our
inability to precisely distinguish the false positive affected from
the true positive asphyxiated or compromised fetus. As a screening
device to aid nurses and physicians, however, these techniques simply
have no peer. With the addition of fetal scalp sampling developed by
Saling, to further delineate fetal health in deviations of heart rate
from normal, we indeed have tools to help identify the fetus with
asphyxia.[23]

The benefit to the author of such a historical review as herein
presented is incalculable. This exercise makes one feel, however,
that we may be, from a relative historical perspective, in a very
primitive period, as regards birth asphyxia prevention. As the world
turns, we are only some 120 years from Little's presentation. With
microprocessors, magnetic chips, ultrasound, and minicomputers
burgeoning in our society, future historical perspective chronicles
will hopefully marvel at how well we did, with so little technical
capacity!

4.Little W. J.: On the Influence of Abnormal Parturition,
Difficult Labours, Premature Birth and Asphyxia Neonatorum on the
Mental and Physical Condition of the Child, Especially in Relation to
Deformity. Trans. Obstet. Soc. London 3:293, 1861.